This invention discloses methods for preparing biocleavable or biodegradable micelle compositions for carrying and releasing drugs and other active agents for therapeutic or other medical uses. Methods are also disclosed for preparing biocleavable cyclodextrin micelle carriers that release drugs under controlled conditions. The invention also discloses methods for preparing biocleavable micelle compositions that are coupled to biorecognition molecules for targeting the delivery of drugs to their site of action.
There is a need for carriers of drugs and active agents that facilitate their solubility, delivery and effectiveness. When drugs are bound to polymers of the prior art they can be taken up at the cell surface by endosomes (receptosomes) and transferred to the lysosomal compartment. This permits modulation of drug uptake through cell surface properties. Also, drug release can be controlled using specific enzymes and other conditions within the cell.
Drugs and other active agents delivered through micelle carriers have gained acceptance as a way for improving cancer chemotherapy and other drug therapies. Also, the prior art now employs drug-antibody or drug-polypeptide conjugates to re-direct anti-cancer and other agents to selected target cells.
Cyclodextrins and their derivatives have been shown to enhance the aqueous solubility of unmodified drugs and reduce the side effects in vivo. Soluble, individual cyclodextrin derivatives such as hydroxypropyl cyclodextrin (HPCD) disclosed by Pitha, U.S. Pat. Nos. 4,596,795 and 4,727,064 and sulfobutylether cyclodextrins (SBECD) disclosed by Stella, et al., U.S. Pat. Nos. 5,134,127 and 5,376,645 have been used as excipients for solubilizing drugs. The NIH currently holds a patent (U.S. Pat. No. 4,727,064) for the improvement of drug preparations using cyclodextrins. However, because individual cyclodextrins and even individual cyclodextrin derivatives easily dissociate from the drug with dilution, many of the advantages of cyclodextrins are limited with parenteral treatment.
The prior art of cyclodextrins has disclosed their use in labeling materials for in vitro testing (Kosak, PCT WO 91/05605, 1991), and in drug preparations (Hirai, et al, U.S. Pat. Nos. 4,523,031 and 4,523,037).
The preparation and use of individual cyclodextrins conjugated to biorecognition molecules as drug carriers is disclosed by Weinshenker, U.S. Pat. No. 5,068,227; 1991, where each coupling site is limited to one drug molecule. However, Weinshenker makes no disclosures or suggestions for any cyclodextrin polymers and they cannot be made with the synthesis methods disclosed. When drugs and other active agents as guest molecules are noncovalently bonded to the individual cyclodextrins of the prior art, they are subject to excessive dissociation, which results in uncontrolled release of drug even before the carriers reach their targets.
Review articles on the pharmaceutical applications of cyclodextrins have identified many problems due to the high turnover rate between inclusion complex formation and dissociation. Stella, V. J., et al., Pharmaccut. Res. 14, 556-567 (1997), report that even with the strongest theoretical binding constants, as soon as the complex of free cyclodextrin and drug is diluted in the bloodstream, over 30% is calculated to dissociate. Also, Rajewski, R., et al, J. Pharm. Sci. 85, 1142-1169(1996), solubilized the anti-cancer drug Taxol(trademark) with cyclodextrins. They reported on page 1145 that xe2x80x9cany attempt to dilute the samples resulted in erratic precipitationxe2x80x9d due to competitive displacement factors found in plasma. Because of these problems, cyclodextrins in the prior art are used for solubilizing and stabilizing certain drugs before or during administration but are not suitable for carrying and delivering drugs in the bloodstream. The cyclodextrin micelle carriers of the instant invention overcome these problems and provide the new function of controlled release, which is not disclosed or suggested by the prior art.
A micelle polymer carrier is a new invention defined herein as a water-soluble (or colloidal) micelle that has been suitably polymerized so that it completely entraps a drug or other active agent within. The formation of micelles for carrying drugs is well known. However, micelle carriers of the prior art suffer from uncontrolled loss of the drug due to diffusion. This invention solves that problem through cross-linking the micelle components to completely entrap the drug until it is delivered to the site of action.
For this invention, any suitable synthesis method now used for preparing drug-carrying micelles, with suitable modification, is applicable to the synthesis of this invention including the disclosures of G. S. Kwon, IN: Critical Reviews in Therapeutic drug Carrier Systems, 15(5):481-512 (1998), and references therein. A distinguishing property of this invention is that the micelle-forming components must have suitable functional groups or biocleavable moieties available on their hydrophilic xe2x80x9cheadsxe2x80x9d to permit cross-linking after the micelle has been formed with a drug inside.
In one preferred embodiment, suitable micelles are formed that contain a drug. Then the hydrophilic head groups are suitably cross-linked using various bifunctional cross-linking agents so that the micelle cannot release the entrapped drug. The preferred embodiment has incorporated cross-links that contain biocleavable linkages as described herein. In another embodiment, the biocleavable micelle includes cyclodextrins or cyclodextrin dimers, trimers or polymers. Also, these micelle carriers can be suitably targeted by coupling suitable biorecognition molecules to the surface.
It has been discovered that the biocleavable micelle of the instant invention overcome the problems of other micelles in the prior art. The instant invention provides new properties and unexpected advantages. In its simplest form, a biocleavable micelle comprises a micelle that has a drug or other active agent completely entrapped within it.
In one embodiment, the biocleavable micelles of the instant invention, by complete entrapment of the active agent, solve the problem of losing drug or other active agent by diffusion when diluted in vivo. In another embodiment, the invention also provides a means for controlled release of the entrapped drug in vivo, which was not possible in the prior art of micelles.
In another embodiment, the invention also provides a means for targeting the biocleavable micelle carrier by coupling it to a biorecognition molecule.
These biocleavable micelle carriers can be used in many fields of medicine to deliver therapeutic drugs and other agents through a variety of routes including orally, nasally and parenterally. Other routes include various applications for delivery through ocular membranes and mucosal membranes, including the use of electric charge as in iontophoresis. They can also be used to deliver nucleic acids such as oligonucleotides to treat various diseases by these routes.